Process for manufacturing nitrobenzodiazepine derivatives

ABSTRACT

WHEREIN X has the same significance as mentioned above. The starting 2-aminomethylindole derivatives are prepared by reacting a nitrophenylhydrazine of the formula,   WHEREIN X signifies a hydrogen or halogen atom, are obtained by reacting with an oxidizing agent, such as chromic acid or the like, a novel 2-aminomethylindole derivative of the formula,   D R A W I N G WHEREIN X has the same significance as mentioned above, converting the indole-2-carboxylic acid derivative to a corresponding amide derivative, dehydrating the amide to a corresponding nitrile derivative, and then reducing the formed nitrile derivatives.   WHEREIN X has the same significance as mentioned above, to give an indole 2-carboxylic acid derivative of the formula,   WITH A PHENYLPYRUVIC ACID DERIVATIVE OF THE FORMULA,   Benzodiazepine derivatives, which have been well known as excellent tranquillizers and which have the formula,   D R A W I N G

iinited States Patent 1 Yamamoto et al.

[ PROCESS FOR MANUFACTURING NHTROBENZODIAZEPINE DERIVATIVES [75]Inventors: Hisao Yamamoto, Nishinomiya; Shigeho Inaba, Takarazuka;Tadashi Okamoto, Ashiya; Toshiyuki l-lirohashi, Kobe; Kikuo lshizumi,Minoo; Michihiro Yamamoto, Takarazuka; lsamu Maruyama,

Minoo; Kazuo Mori, Kobe; Tsuyoshi Kobayashi, Minoo, all of Japan [73]Assignee: Sumitomo Chemical Company, Ltd.,

' Osaka, Japan [22] Filed: Apr. 6, 1971 [21] Appl. No.: 131,767

Related U.S. Application l)ata [62] Division of Ser. No. 770,815, Oct.25, 1968, Pat. No.

Primary Examiner-Alex Maz el Assistant ExaminerJoseph A. NarcavageAttorney-Stevens, Davis, Miller & Mosher [57] ABSTRACT Benzodiazepinederivatives, which have been well known as excellent tranquillizers andwhich have the formula,

N02 H H 0 wherein X signifies a hydrogen or halogen atom, are obtainedby reacting with an oxidizing agent, such as chromic acid or the like, anovel Z-aminomethylindole [4 1 Mar. 27, 1973 derivative of the formula,

N0 II wherein X has the same significance as mentioned above.

The starting 2-aminomethylindole derivatives are prepared by reacting anitrophenylhydrazine of the formula,

with a phenylpyruvic acid derivative of the formula,

wherein X has the same significance as mentioned above, to give anindole 2-carboxylic acid derivative of the formula,

wherein X has the same significance as mentioned above, converting theindole-Z-carboxylic acid derivative to a corresponding amide derivative,dehydrating the amide to a corresponding nitrile derivative, and thenreducing the formed nitrile derivatives.

1 Claim, N0 Drawings PROCESS FOR MANUFACTURING NITROBENZODIAZEPINEDERIVATIVES This application is a division of my co-pending application,Ser. No. 770,815, filed Oct. 25, 1968, now US. Pat. No. 3,658,809.

BACKGROUND OF THE INVENTION 1. Field of the Invention This inventionrelates to a process for producing benzodiazepine derivatives. Moreparticularly, the invention pertains to a process for preparingbenzodiazepine derivatives having prominent effects as tranquillizers,muscle-relaxants, spasmolytics, and hypnotics which are represented bythe formula,

wherein X signifies a hydrogen or halogen atom.

2. Prior Arts The benzodiazepine derivatives represented by the formula[I] are compounds well known as prominent tranquilizers,muscle-relaxants, dispasmolytics and hypnotics (cf. L. H. Sternbach etal.: J. Med. Chem., 6 261). As methods for producing the benzodiazepinederivatives, several processes have been known. For example, abenzodiazepine derivative is obtained in a poor yield by reacting a2-aminobenzophenone derivative with glycine hydrochloride or glycineethyl ester (German Pat. No. 1,145,626).

A benzodiazepine derivative is also prepared by treating thebromoacetamide derivatives of aminonitrobenzophenone with ammonia andcyclizing the resulting aminoacetamide derivatives. (cf. L. H. Sternbachet al.: J. Med. Chem., 6 261; German Pat. No. 1,136,709)

A 7-nitro-benzodiazepine derivative is also prepared by direct nitrationof benzodiazepine derivative with a mixture of concentrated sulfuricacid and potassium nitrate. (cf. L. H. Sternbach et al.: ibid; GermanPat.

DISCLOSURE OF THE INVENTION The inventors have found that thebenzodiazepine derivatives of the formula [I] can be obtainediin highyields by reacting with an oxidizing agent, a 2- aminomethylindolederivative, or its salt, represented by the formula,

NO: l

wherein X has the same significance as mentioned before.

Such surprising process from a 5-membered ring compound to a 7-memberedring compound due to ring expansion reaction has not heretofore beendescribed in any literature. Therefore, the novel process of the presentinvention is unobvious from the known method of the similar processes,and moreover very much use ful and unexpected procedure.

The 2-aminomethylindole derivatives employed as starting materials inthe above reaction are novel compounds, and are easily prepared, forexample, by hydrogenating corresponding indole-2-carbonitrilederivatives. Further, the above-mentioned indole-Z- carbonitrilederivatives also are novel compounds, and are obtained, for example, bythe amidation of free indole-2-carboxylic acid derivatives followed bydehydration of the resultant amide derivative. Still further, the saidindole-2-carboxylic acid derivatives also are novel compounds, and areobtained from, for example, nitrophenylhydrazine and phenylpyruvic acidderivatives.

The all of the above-mentioned compounds can be prepared smoothly and inhigh yields. Accordingly, the present process is markedly useful as apractical process for the production of the aforesaid benzodiazepinederivatives represented by the formula A primary object of the presentinvention is to provide a process for the advantageous production of thebenzodiazepine derivatives represented by the formula Another object isto provide novel indoIe derivatives and processes for the preparationthereof.

Other objects will be apparent from the following description.

2-An1in0methylindole derivative Benzodiazepine derivative In the aboveequations, R is an alkyl group having 1-4 carbon atoms, e.g., a methyl,ethyl, isopropyl or tertiary butyl group; R is an alkyl group .having 14carbon atoms, e.g., a methyl or ethyl group; R is R or a hydrogen atom;X is a hydrogen or halogen atom, e.g. a chlorine, bromine or fluorineatom; and Y is a halogen atom, e.g. a chlorine or bromine atom.

The present process will be illustrated in detail as follows.

[A] Preparation of Phenylhydrazone derivative [VII] The phenylhydrazonederivative [VII] employed in the present process is a novel compound,and is prepared either by reacting a corresponding nitrophenylhydrazinederivative [III], or an acid salt thereof, with the phenylpyruvic acidderivative [IV], or by reacting the nitrobenzenediazonium compound [V]with the ester of a-benzyl-B-keto-acid derivative [VI]. In the case ofthe latter reaction, the resulting phenylhydrazone derivatives are onlythose of the formula [VII] in which R is identical with R, and containno hydrogen. That is, there are obtained phenylhydrazone derivativesrepresented by the formula,

[VIIa] The reaction of nitrophenylhydrazine [III] with phenylpyruvicacid derivative [IV] is explained below.

The phenylhydrazone derivative [VII] is obtained by reacting thenitrophenylhydrazine [III], or an acid salt thereof, with thephenylpyruvic acid derivative [IV]. The reaction is preferably carriedout in the presence of an inert solvent such as lower alkanols, e.g.,methanol, ethanol and the like. The reaction temperature is notparticularly limited, but is ordinarily within the range of from roomtemperature to the boiling point of the solvent employed. Examples ofthe acid salt of nitrophenylhydrazine include an inorganic acid saltsuch as hydrochloride, hydrobromide or sulfate, or an organic acid saltsuch as acetate or oxalate. The nitrophenylhydrazine [III] or a saltthereof is used in an equimolar amount or more of the phenylpyruvic acidderivative.

Examples of the phenylhydrazone derivatives[VIl] obtained by process ofthe present invention, include the following compounds:

methyl phenylpyruvate p-nitrophenylhydrazone ethyl phenylpyruvatep-nitrophenylhydrazone tertiary butyl phenylpyruvatep-nitrophenylhydrazone phenylpyruvic acid p-nitrophenylhydrazonephenylpyruvic acid m-nitrophenylhydrazone phenylpyruvic acido-nitrophenylhydrazone (o-chlorophenyl )pyruvic acidp-nitrophenylhydrazone (o-fluorophenyl )pyruvic acidp-nitrophenylhydrazone (o-bromophenyl )pyruvic acidp-nitrophenylhydrazone (p-chlorophenyl )pyruvic acidp-nitrophenylhydrazone (m-chlorophenyl )pyruvic acidp-nitrophenylhydrazone ethyl (o-chlorophenyl)pyruvatep-nitrophenylhydrazone The phenylhydrazone derivative [Vlla] may beobtained by reacting the ester of a-benzyl-B-keto-acid derivative [VI]with the nitrobenzenediazonium compound [V] in a suitable solvent, e.g.,water, methanol,

ethyl (o-chlorophenyl)pyruvate p-nitrophenylhydrazone ethyl(o-bromophenyl)pyruvate p-nitrophenyl- I hydrazone ethyl(o-fluorophenyl)pyruvate p-nitrophenyl- V hydrazone -ethyl(p-chlorophenyl)pyruvate p-nitrophenylhydrazone ethyl(m-chlorophenyl)pyruvate p-nitrophenylhydrazone Although two isomers(Syn and anti forms) of the phenylhydrazone derivative [VII] areobserved both isomers can be used for the next reaction step.

[B] Preparation of indole-2-carboxylic acid derivative [VIII]:

The indole-2-carboxylic acid derivative [VIII] is obtained by treatingthe phenylhydrazone derivative [VII] with an acid, in a suitablesolvent.

As the solvent, there is used, for example, a lower alkanol such asmethanol, ethanol, isopropanol or tertiary butanol; an aromatichydrocarbon such as benzene, toluene or xylene; an organic acid such asformic or acetic acid; or other organic solvent such as chloroform orcyclohexane. An organic acid such as formic or acetic acid, or analcohol is particularly preferable for the reaction.

As the acid, there is used, for example, a mineral acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid andpolyphosphoric acid, organic acid such as formic acid and acetic acid orother acidic reagents, including Lewis acids such as zinc chloride, ironchloride, aluminum chloride and boron fluoride. The reaction isgenerally effected at elevated temperature.

In the present invention, examples of the indole-2- carboxylic acidderivative [VIII] include the following compounds:

5-nitro-3-phenyl-indole-Z-carboxylic acid ethyl5-nitro-3-phenyl-indole-2-carboxylate methyl5-nitro-3-phenyl-indole-2-carboxylate tertiary butyl5-nitro-3-phenyl-indole-2-carboxylate ethyl 6 (or 4)nitro-3-phenyl-indole-2-carboxylate 7-nitro-3-phenyl-indole-2-carboxylic acid 3-(o-chlorophenyl)-S-nitro-indole-2-carboxylic acid3-(o-bromophenyl)-5-nitro-indole-2-carboxylic acid3-(o-fluorophenyl)-5-nitro-indole-2-carboxylic acid3-(m-chlorophenyl)-5-nitro-indole-2-carboxylic acid3-(p-chlorophenyl)-5-nitro-indole-2-carboxylic acid Theindole-2-carboxylic acid derivative [VIII] can also be directlyobtained, by reacting the nitrophenylhydrazine [III], or a salt thereof,with the phenylpyruvic acid derivative [IV].

The reaction can be carried out in a solvent, for example, an alkanolsuch as methanol, ethanol, isopropanol and tertiary butanol, aromatichydrocarbon such as benzene, toluene, xylene, and the like, organic acidsuch as formic acid and acetic acid, and the like, or an other inertorganic solvent such as acetone, chloroform, cyclohexane, and the like,preferably in the presence of an acid catalyst, for example, mineralacid such as hydrogen chloride, hydrogen bromide, sulfuric acid,phosphoric acid, polyphosphoric acid, and the like, organic acid such asformic acid and acetic acid, Lewis acid such as zinc chloride, ironchloride, aluminum chloride, boron fluoride, and the like, or cationexchange resin.

As the salt of phenylhydrazine derivative [III], there may be used, forexample, an inorganic salt such as hydrochloride, hydrobromide orsulfate; or an organic acid salt such as acetate or oxalate.

The reaction is effected under conditions similar to that of theabove-mentioned preparation from the phenylhydrazone derivative toZ-carboxylic acid derivative [VIII]. However, when the reaction iscarried out under mild conditions, the phenylhydrazone derivative [VII]is obtained. In this case, isolation of the compound [VII] is notnecessarily required for this cyclization reaction.

In the present invention, examples of the indole-2- carboxylic acidderivative [VIII] include the following compounds:

5 -nitro-3-phenyl-indole-2-carboxylic acid methyl5-nitro-3-phenyl-indole-Z-carboxylate Q cooni N02 [VIIIa] wherein R andX have the same significances as men tioned before, by reacting thenitrobenzenediazonium compound [V] with the ester ofa-benzyl-B-keto-acid derivative [VI].

According to the above process, the ester of abenzyl-B-keto-acidderivative represented by the formula [VI] is allowed to react with thesaid diazomium compound represented by the formula [V] in a suitablesolvent, e.g., water, methanol or ethanol, in the presence of a base,e.g., caustic soda, caustic potash, potassium carbonate, sodiummethylate sodium ethylate, sodium acetate, potassium acetate or thelike, whereby the reaction proceeds smoothly.

Because of unstability of the benzene diazonium salt, it is preferableto carry out the reaction below l0C., more preferably below 5C.Thereafter, treatment of the reaction product with an acid causesformation of the ester of indole-2-carboxylic acid derivativerepresented by the aforesaid formula [VIIIa]. However, an intermediateproduced during this reaction is preferably once isolated and treatedwith an acid in an organic solvent to yield very readily the aimed esterof indole-2-carboxylic acid derivative [VIIa] in good yield. In thisreaction, an acid, for example, mineral acid such as hydrogen chloride,hydrogen bromide, sulfuric acid, phosphoric acid, polyphosphoric acid,and the like, or other Lewis acid such as zinc chloride, ferrouschloride, aluminum chloride, stannous chloride, boron fluoride and thelike is suitable.

In this reaction, following solvents are most useful, for example,alkanols such as methanol, ethanol and isopropanol, aromatichydrocarbons such as benzene, toluene and xylene, organic acids such asformic acid and acetic acid, or common organic solvents such as acetone,chloroform and cyclohexane.

In the present invention, examples of the indole-2- carboxylic acidderivative [VIIIa] include the following compounds:

methyl 5-nitro-3-phenyl-indole-2-carboxylate ethylS-nitro-3-phenyl-indole-2-carboxylate tertiary butyl5-nitro-3-phenyl-indole-2-carboxylate ethyl 6 (or4)-nitro-3-phenyl-indole-Z-carboxylate ethyl7-nitro-3-phenyl-indole-2-carboxylate ethyl3-(o-chlorophenyl)-5-nitro-3-indole-2-carboxylate ethyl3(o-bromophenyl)-5=nitro-3-indole-2-carboxy- -COOH N02 [VIIIb] wherein Xhas the same significance as mentioned before.

The above process is effected by treating the. aforesaidindole-2-carboxylic acid derivative of the formula [Vllla] in a solventin the presence of a hydrolyzing agent.

As the solvent, there is used water or a lower alkanol such as methanol,ethanol or isopropyl alcohol. An organic solvent, for example, loweralkanol, acetone, tetrahydrofuran, ethylene glycol or the like can beused in the presence of water for the reaction.

As a hydrolyzing agent, there is used an alkali metal such as sodium,potassium or lithium; an alkali metal hydroxide such as sodium hydroxideor potassium hydroxide; an alkali metal carbonate such as sodiumcarbonate or potassium carbonate; an alkaline earth metal hydroxide suchas barium hydroxide or calcium hydroxide; or an ammonia compound such asammonium hydroxide. However, the use of an alkali metal or alkalineearth metal hydroxide is particularly preferable. The reaction proceedsat room temperature but is When R is a tertiary butyl group, theindole-2-carboxylic acid derivative [Vllla] can also be converted to thedesired carboxylic acid [Vlllb] by heating it with a mineral acid ortoluenesulfonic acid. The desired substance can be obtained also as ametal salt or an ammonium salt.

In the present invention, examples of the indole-2- carboxylic acidderivative [Vlllb] include the following compounds:

5 -nitro-3-phenyl-indole-2-carboxylic acid 6 (or4)-nitro-3-phenyl-indole-Z-carboxylic acid7-nitro-3-phenyl-indole-Z-carboxylic acid5-nitro-3-(o-chlorophenyl)-ind0le-2-carboxylic acid5-nitro-3-(o-fluorophenyl)-indole-2-carboxylic acid 5-nitro-3-(mchlorophenyl)-indole-2-carboxylic acid 5-nitro-3-(p-chlorophenyl)-indole-2-carboxylic acid It is needless to saythat the indole-2-carboxylic acid derivative [Vlllb] can also bedirectly obtained either from a phenylhydrazone derivative, in which Rof [Vll] is a hydrogen atom, i.e. a phenylhydrazone represented by theformula,

l0 [VIIbl or by reacting the nitrophenylhydrazine derivative of theformula [III] with a compound represented by the formula,

-cm -ooorr [IVb] [C] Preparation of indole-2-carboxamide derivative Inthe present invention, the indole-2-carboxamide derivative [X] is anovel compound, and is obtained by reacting the aforesaidindole-2-carboxylic acid derivative [Vlllb] with a halogenating agent inthe presence or absence of an inert solvent to theindoIe-2-carboxylichalide derivative [IX] and then reacting the saidhalide derivative with ammonia.

In this halogenation reaction, there is used an inert solvent, such asbenzene, toluene, chloroform, methylene chloride or carbontetrachloride.

I-lalogenating agents include thionyl chloride, phosphorus trichloride,phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride,phosgene and the like. The reaction rate may be accelerated by adding abasic reagent such as pyridine or dimethylformamide. Further, thestarting indole-2-carboxylic acid derivative [Vlllb] may be used eitherin the form of a free carboxylic acid or in the form of a metal saltsuch as sodium salt.

45 After removing the solvent and excess of reacting agents, thereaction product is obtained, if necessary, by treatment such asextraction with an inert solvent to give the objective product. In thiscase, isolation or further purification of this product is not alwayseasy. However, in leading the indole -2-carboxylic halide, for example,to indole-2-carboxylic acid amide, isolation or purification is notalways necessary and crude products or a reaction mixture can be used asit is for carrying out the reaction. In the above manner, a chloride,bromide or the like is obtained.

In the present invention, examples of the indole-2- carboxylic halidederivative [IX] include the following compounds:

5-nitro-3-phenyl-indole-2-carboxylic chloride 6 (or4)-nitro-3-phenyl-indole-2-carboxylic chloride.

7-nitro-3-phenyl-indole-2-carboxylic chloride5-nitro-3-phenyl-indole-2-carboxylic bromide3-(o-bromophenyl)-5-nitro-indole-2-carboxylic chloride3-(o-fiuorophenyl)-5-nitro-indole-2-carboxylic chloride3-(p-chlorophenyl)-5-nitro-indole-2-carboxylic chloride3-(m-chlorophenyl)-5-nitro-indole-2-carboxylic chloride The amidation ofan indole-2-carboxylic halide derivative [IX] is preferably effected inthe presence of a solvent. As the solvent, there can be used a loweralkanol such as methanol or ethanol; or an organic solvent such asether, acetone, benzene, toluene, xylene, chlorobenzene, chloroform orthe like.

In the present reaction, ammonia can be used by introducing gaseousammonia to a reaction mixture or adding alcoholic ammonia (such asmethanolic ammonia, ethanolic ammonia) or aqueous ammonia to a reactionmixture.

Since the reaction proceeds at room temperature, heating or cooling isnot always required. If desired, however, the reaction may be controlledby heating or cooling.

The indole-2-carboxamide derivatives [X] have central nervous depressantactivities.

In the present invention, examples the indole-2carboxamide derivative[X] include the following compounds:

-nitr0-3-phenyl-indole-2-carboxamide 6 (or 4)-nitro-3-phenyl-indole-2-carboxamide 7-nitro-3 -phenyl-indole-2-carboxamide 3-(o-chlorophenyl)-5-nitro-indole-Z-carboxamide3-(o-bromophenyl)-5 -nitro-indole-2-carboxamide3--(o-fluorophenyl)-5-nitro-indole-2-carboxamide3-(p-chlorophenyl)-5-nitro-indole-2-carboxamide 3-(m-chlorophenyl)-5-nitro-indole-2-carboxamide [D] Preparation ofindole-2-carbonitrile derivative In the present invention, the novelindole-2-carbonitrile derivative [XI] may be prepared by dehydrating theindole-2-carboxamide derivative [X]. The dehydration of theindole-Z-carboxamide [X] is effected by heating the same, preferably inthe presence of a dehydrating agent. As the dehydrating agent, there canbe used, for example, a phosphorus halide such as phosphorusoxychloride, phosphorus trichloride or phosphorus pentachloride; or anacid chloride such as p-toluenesulfonyl chloride, methyl sulfonylchloride, acetyl chloride, thionyl chloride, benzoyl chloride orcarbobenzyloxy chloride. The reaction is carried out in the presence orabsence of a solvent. The dehydrating agent itself may be used as thesolvent. After completion of the reaction, the desired product isisolated from the solvent and the dehydrating agent.

In the present invention, examples of indole-2-carbonitrile derivative[XI] include the following compounds:

5-nitro-3-phenyl-indole-2-carbonitrile 6 (or4)-nitro3-phenyl-indole-2-carbonitrile7-nitro-3-phenyl-indole-2-carbonitrile3-(o-chlor0phenyl)-5-nitro-indole-2-carbonitrile3-(o-bromophenyl)-5-nitro-indole-2-carbonitrile3-(o-fluorophenyl)-5-nitro-indole-2-carbonitrile 3-(p-chlorophenyl)-6-nitro-indole-2-carbonitrile3-(m-chlorophenyl)-5-nitro-indole-2-carbonitrile [B] Preparation of2-aminomethylindole derivative [II] In the present invention, the novelZ-aminomethylindole derivative [II] or its salt is prepared by reducingthe indole-2-carbonitrile derivative [XI]. The reduction is effected byreacting the indole-2-carbonitrile derivative [XI] with a suitablereducing agent in a solvent.

The reducing agent, which may selectively reduce the cyano group to anaminomethyl group, without effecting the nitro group and/or halogenatom, can be used.

Examples of the reducing agent usable in the present invention includeboron hydrides such as diborane, aluminum borohydride, calciumborohydride and sodium trimethoxy borohydride, and sodium borohydridesincorporated with metal halides such as aluminum halides. Particularly,the diborane is preferably used. When diborane is used as reducing agentgaseous diborane is introduced into the reaction mixture, or diborane isaccured in the reaction system. For example, the reduction is effectedby using diborane generated from sodium borohydride and borontrifuloride or mercurous chloride in the reaction system. In thereduction by diborane, solvent such as ether, tetrahydrofuran, dioxanedyglyme or the like can be preferably used. Generally, the reaction iseffected at a temperature within the range from room temperature to theboiling point of the solvent employed. After completion of the reaction,excess of reducing agent is decomposed for example by addition of wateror an acid such as hydrochloric acid. The 2-amino methylindolederivative [II] may be obtained as the corresponding salt by treatmenton an inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitricor phosphoric acid, or an organic acid such as acetic or formic acid.The 2-aminomethylindole derivatives [II] and salts thereof showhypoglycemic activity.

In the present invention, examples of the 2- aminomethyl indolederivative [II] include the following compounds:

2-aminomethyl-5-nitro-3-phenyl-indole 2-aminomethyl-6 (or4)-nitro-3-phenyl-indole 2-aminomethyl-7-nitro-3-phenyl-indoleZ-aminomethyl-3-(o-chlorophenyl)-5-nitro-indole2-aminomethyll3-(o-bromophenyl)-5-nitro-indole2-aminomethyl3-(o-fluorophenyl)-5-nitro-indole2-aminomethyl-3-(m-chlorophenyl)-5-nitro-indole2-aminomethyl-3-(p-chlorophenyl)-5-nitro-indole and thesehydrochlorides, hydrobromides, sulfate, phosphate and acetates.

[F]Production of benzodiazepine derivative [I] According to the presentfinal process, a benzodiazepine derivative [I] is produced from the 2-aminomethylindole derivative [II] or a salt thereof.

In carrying out the process for preparing the benzodiazepine derivativesaccording to the present invention, 2-aminomethylindole derivativesrepresented by the formula [II] or their salts are reacted with anappropriate oxidizing agent, for example, ozone, hydrogen peroxide,peracid (e.g., performic acid, peracetic acid and perbenzoic acid),chromic acid and potassium permanganate. The oxidizing agent used in theprocess of the invention is not limited, however, only to thoseexemplified above. The reaction is generally readily effected at roomtemperature. Higher or lower temperature is sometimes found moresatisfactory.

Chromium trioxide is preferred as oxidizing agent. The reaction maypreferably be carried out in the presence of a solvent. The solventdepends upon the oxidizing agents used, and is selected from water,acetone, carbon tetra-chloride, acetic acid, sulfuric acid and any ofthe other solvents which do not react substantially with any of thereactants. The oxidizing agent is used in a stoichiometric amount ormore. The reaction temperature used depends upon the oxidizing agentused.

In the case which the oxidation is carried out using chromium trioxidein the presence of acetic acid, it is preferable to use 2-3 3 times astoichiometric amount of chromium trioxide and to conduct the reactionat room temperature. A 2-aminomethylindole derivative or its salt suchas hydrochloride, hydrobrornide, sulfate, nitrate, acetate and the likeis dissolved or suspended in a solvent and an oxidizing agent is addedthereto with stirring. The reaction is generally completed within about24 hours.

In the present invention, the benzodiazepine derivative [I] may be takenup asan acid addition salt by treatment with an inorganic acid such ashydrochloric, sulfuric, or nitric acid; or an organic acid such asmaleic, fumaric, succinic, formic or acetic acid.

Examples of the benzodiazepine derivative obtained according to thepresent process include the following compounds.

benzodiazepine-2-one 5 -pheny1-8-nitro-1 ,3-dihydro-2H-1 ,4-

benzodiazpine-Z-one 5-phenyl-9-nitro-1 ,3-dihydro-2H- 1 ,4-

benzodiazepine-2-one 5-(o-chlorophenyl)-7-nitro-1 ,3-dihydro-21-I- 1 ,4-

benzodiazepine-Z-one 5-(o-bromophenyl)-7-nitro-1,3-dihydro-2H-l ,4-

benzodiazepine-2-one 5 -(o-fluorophenyl)-7-nitro-1,3-dihydro-2I-l-1,4-

benzodiazepine-Z-one 5-(m-chlorophenyl)-7-nitroo1 ,3-dihydro-2I-I-1 ,4-

benzodiazepine-2-one 5-(p-chlorophenyl)-7-nitro-1 ,3-dihydro-2H-1 ,4-

benzodiazepine-Z-one.

EXAMPLE 1 To a solution of 22.5 g. of phenylpyruvic acid in 500 ml. ofethanol is added 21 g. of p-nitrophenylhydrazine and the mixture isheated under reflux for 30 min. After the reaction is complete, thesolvent is removed under reduced pressure to give phenylpyruvic acidpnitrophenylhydrazone quantitatively.

The following compounds are similarly prepared:

methyl phenylpyruvate p-nitrophenylhydrazone ethyl phenylpyruvatep-nitrophenylhydrazone tertiary butyl phenylpyruvatep-nitrophenylhydrazone phenylpyruvic acid m-nitrophenylhydrazonephenylpyruvic acid o-nitroph enylhydrazone (o-chlorophenyl )pyruvic acidp-nitrophenylhydrazone (o-fluorophenyl )pyruvic acidp-nitrophenylhydrazone (o-bromophenyl )pyruvic acidp-nitrophenylhydrazone (p-chlorophenyl )pyruvic acidp-nitrophenylhydrazone (m-chlorophenyl )pyruvic acidp-nitrophenylhydrazone EXAMPLE 2 To a solution of 22.5 g. ofphenylpyruvic acid in 500 ml. of ethanol is added 21 g. ofp-nitrophenylhydrazine and the mixture was heated under reflux for 30min. The resultant mixture is concentrated and then cooled. Theprecipitate is collected by filtration to give 12 g. of the a isomer ofphenylpyruvic acid p-nitrophenylhydrazone, one of two isomers.Recrystallization from ethanol gives pale yellow fine needles, mp. 191192C. (decomp.)

IR cm": v-. 3260 (in Nujol); v l669 (in Nujol) UV )l,,,,,,""": 382 mp.(2 31,100)

The filtrate is further concentrated to give 28 g. of another isomer,the B form of phenylpyruvic acid pnitro-phenylhydrazone, m.p. 177 179C.Recrystallization from benzene gives yellow fine needles, m.p.

185- 186C. (decomp.)

UV: A 372 mp. (e 28,800)

EXAMPLE 3 To an ice cold solution of 150 g. of ethyl abenzylacetoacetatein 700 ml. of ethanol is added portionwise 236 ml. of 50 percent aqueouspotassium hydroxide solution under cooling, and then 1390 ml. ofice-water is added to the mixture. To this mixture is added dropwise, acold diazonium salt solution prepared from 96 g. of p-nitroaniline, 278ml. of conc. hydrochloric acid, 278 ml. of water and a solution of 48'g. of sodium nitrite in 140 ml. of water. After addition, the reactionmixture is stirred for 10 min. under cooling, and extracted with ether.The ethereal layer is dried over sodium sulfate and the ether isevaporated to give 216 g. (96.6 percent) of ethyl phenylpyruvatepnitrophenylhydrazone as an oil, which is partially solidified onstanding overnight. The solid is recrystallized from ethanol to give thea isomer having mp. 114C.

IR v cm": 3330 (NH); 1729 (C0) Anal. Calcd. for C -,I-I O.,N C, 62.38;H, 5.24; N,

12.83%. Found: C, 62,35; H, 5.14; N, 12,72%.

To a solution of 1 11.1 g. of the said crude oily ethyl phenylpyruvatep-nitrophenylhydrazone in 400 m1. of ethanol is introduced dry gaseoushydrogen chloride for 40 min., while the temperature is arised to 64C.

The mixture is cooled and filtered to give 49.8 g. of the B isomer ofthe ethyl phenylpyruvate p-nitrophenylhydrazone, m.p. 121 124C.Recrystallization from ethanol gives the product of m.p. 125.5 129.5C.

Anal. Calcd. fOl' C 7H17O4N3l C, H, N,

Found: C, 62.44; H, 4.93; N, 12.64%.

The following compounds are similarly prepared;

methyl phenylpyruvate p-nitrophenylhydrazone ethyl phenylpyruvatep-nitrophenylhydrazone tertiary butyl phenylpyruvatep-nitrophenylhydrazone ethyl phenylpyruvate m-nitrophenylhydrazone ethyl(o-chlorophenyDpyruvate p-nitrophenylhydrazone ethyl(o-bromophenyl)pyruvate p-nitrophenylhydrazone ethyl(o-fluorophenyl)pyruvate p-nitrophenylhydrazone ethyl(p-chlorophenyl)pyruvate p-nitrophenylhydrazone ethyl(m-chlorophenyl)pyruvate p-nitrophenylhydrazone EXAMPLE4 A suspension of40 g. of phenylpyruvic acid pnitrophenylhydrazone in 1.5 l of 50 percentfurmic acid is heated under reflux for 4 hours. The solvent is removedunder reduced pressure, and the residue is washed with ethanol to give37 g. of 5-nitro-3-phenylindole-2-carboxylic acid. Recrystallizationfrom ethanol gives orange yellow crystals, m.p. 299C. (decomp.).

EXAMPLE 5 A suspension of l g. of the B isomer of ethyl phenylpyruvatep-nitrophenylhydrazone in 40 ml. of 50 percent furmic acid is heatedunder reflux for 4 hours. The solvent is removed under reduced pressureand the residue is washed a small amount of ethanol to give 0.75 g. ofethyl 5-nitro-3-phenyl-indole-2-carboxylate, m.p. 235- 237C. (decomp.).

EXAMPLE 6 A mixture of 32.7 g. of ethyl phenylpyruvatepnitrophenylhydrazone, 200 ml. of acetic acid and 200 ml. of conc.hydrochloric acid is heated under reflux for 2 hours. After cooling, thesolid is collected by filteration, washed with water to give 23.8 g. ofethyl 5- nitro-3-phenylindole-2-carboxylate.

The following compounds are similarly prepared:

methyl 5-nitro-3-phenyl-indole-2-carboxylate tertiary butyl5-nitro-3-phenyl-indole-2-carboxylate ethyl 6 (or4)-nitro-3-phenyl-indole-2-carboxylate7-nitro-3-phenyl-indole-2-carboxylic acid3-(o-chlorophenyl)-5-nitro-indole-2-carboxylic acid3-(p-bromophenyl)-5-nitro-indole-2-carboxylic acid 3-(o-fluorophenyl)-5-nitro-indole-2-carboxylic acid3-(m-chlorophenyl)-5-nitro-indole-2-carboxylic acid3-(p-chlorophenyl)-5-nitro-indole-2-carboxylic acid EXAMPLE 7 A mixtureof 7.1 g. of p-nitroaniline, 20.9 g. of conc. hydrochloric acid and 20ml. of water is heated into a solution, and then cooled to C. To themixture is added dropwise a solution of 3.7 g. of sodium nitrite in 7ml. of water below 0C., and the mixture is stirred for 10 min. To themixture is added 11.7 g. of sodium acetate and the mixture is stirredfor 30 min. below C. The resultant mixture is added dropwise to anice-cold solution of 11 g. of ethyl abenzylacetoacetate and 14.7 g. ofanhydrous potassium acetate in methanol below 3C., and stirring iscontinued for additional 2 hours below C. The reaction mixture isextracted with 200 ml. of ither. The ethereal layer is washed withwater, dried over sodium sulfate and evaporated to an oil.

To the oily residue is added 50 ml. of isopropyl-alcohol and 50 ml. ofconc. hydrochloric acid and the mixture is heated under reflux for 5hours. After cooling the precipitate is collected by filteration, washedwith water and dried to give 8.8 g. of ethyl 5-nitro-3-phenyl-indole-Z-carboxylate.

Example 8 A mixture of 7.1 g. of p-nitroaniline, 20.9 g. of conc.hydrochloric acid and 20 ml. of water is heated into a solution, andthen cooled to 0C. The mixture is diazotized by adding dropwise asolution of 3.7 g. of sodium nitrate in 7 ml. of water below 0C. To themixture is added 1 1.7 g. of sodium acetate and the mixture is stirredfor 30 min. below 5C. The resultant mixture is added dropwise to anice-cold solution of 11 g. of ethyl a-benzylacetoacetate and 14.7 g. ofanhydrous potassium acetate in methanol below 3C. with stirring. Thereaction mixture is stirred for 1 hour below 10C., and heated underreflux 4 hours. After cooling, the solid is separated and taken up withmethanol and water to give ethyl phenylpyruvate p-nitrophenylhydrazone(14.5 g.), m.p. 108- 117C.

This hydrazone is heated with 45 ml. of isopropyl-alcohol and 45 ml. ofconc. sulfuric acid. After reflux for 5 hours, the reaction mixture iscooled. The solid is collected by filtration, washed with water anddried to give 10.5 g. of ethyl 5-nitro-3-phenyl-indole-2-carboxylate,m.p. 2l8C.

The following compounds are similarly prepared:

methyl 5-nitro-3-phenyl-indole-2-carboxylate tertiary butyl5-nitro-3-phenyl-indole-2-carboxylate ethyl 6 (or4)-nitro-3-phenyl-indole-2-carboxylate ethyl7-nitro-3-phenyl-indole-2-carboxylate ethyl3-(o-chlorophenyl)-5-nitro-indole-2-carboxyetl s' l3-(o-bromophenyl)-5-nitro-indole-2-carboxyetl' i y l3-(o-fluorophenyl)-5-nitro-indole-2-carboxyetl i y l3-(m-chlorophenyl)-5-nitro-indole-2-carboxyenisi3-(p-chlorophenyl)-5-nitro-indole-2-carboxyate EXAMPLE 9 To a solutionof 22.5 of phenylpyruvic acid in 500 ml. of ethanol is added 21 g. ofp-nitrophenylhydrazine. The mixture is refluxed for 30 min. and thesolvent is evaporated. To the residue is added 1.5 l of 50 percentformic acid and the mixture is heated under reflux for 4 hours. Thesolvent is removed under reduced pressure and the residue is washed withethanol to yield S-nitro- 3-phenyl-indole-2-carboxylic acid, m.p. 297C.(decomp.), quantitatively. Recrystallization from ethanol gives orangeyellow crystals, m.p. 299C. (decomp.).

Anal. Calcd. for C H O N C, 63.83; H, 3.57; N,

9.92%. Found: C, 63.40;'H, 3.51; N, 10.02%.

EXAMPLE 10 A mixture of 25 g. of phenylpyruvic acid, 23 g. ofpnitrophenylhydrazine, 480 ml. of acetic acid and 450 ml. of conc.hydrochloric acid is heated for 2 hours. The reaction mixture is cooledand then poured into ice-water. The precipitate is collected byfiltration,

EXAMPLE 1 1 To a solution of 112.6 g. of p-nitrophenylhydrazine and 119.2 g. of phenylpyruvic acid in 2 l of acetic acid is added 2 l ofconc. hydrochloric acid with stirring. The mixture is heated (to 93C.)under reflux for 1 hour and then cooled. The precipitate is collected byfiltration, washed with water and dried to yield 168.2 g.

of 5-nitro-3-phenyl-indole-Z-carboxylic acid, m.p.

EXAMPLE 12 To a solution of 2.7 g. of potassium hydroxide in 50 ml. ofisopropyl alcohol and 1 ml. of water is added 6.2 g. of ethyl5-nitro-3-phenyl-indole-2-carboxy1ate and the mixture is heated underreflux for 4.5 hours.

The mixture is concentrated and the residue is dissolved in water. Thecooled solution is made acidic with cone. hydrochloric acid undercooling. The precipitate formed is collected by filtration, washedthoroughly with water and dried to give 5.5 g. of 5- nitro-3phenyl-indole-2-carboxylic acid, m.p. 287C. (decomp.).

The following compounds are similarly prepared:

6 (or 4)-nitro-3 phenyl-indole-Lcarboxylic acid7-nitro-3-phenyl-indole-2-carboxylic acid 5-nitro-3-(o-chlorophenyl)-indole-2-carboxylic acid5-nitro-3-(o-fluorophenyl)-indole-2-carboxylic acid5-nitro-3-(m-chlorophenyl)-indole-2-carboxylic acid5-nitro-3-(p-chlorophenyl)-indo1e-2-carboxylic acid EXAMPLE 13 A mixtureof 163.1 g. of 5-nitro-3-phenyl-indole-2- carboxylic acid and 420 ml. ofthionyl chloride is heated under reflux for 1 hour. The excess ofthionyl chloride is removed under reduced pressure to give 5-nitro-3-phenyl-indole-2-carboxylic chloride quantitatively.

This product is confirmed by the following process. To the suspension ofthis crude 5-nitro-3-phenyl-indole-2-carboxylic chloride in 2 l of drytoluene is introduced gaseous ammonia. The precipitate is collected byfiltration, washed with water and dried to give5-nitro-3-phenyl-indole-2-carboxamide quantitatively, m.p. 291 293C.

The following compounds are similarly prepared:

6-(or 4)-nitro-3-phenyl-indole-2-carboxylic chloride7-nitro-3-phenyl-indole-Z-carboxylic chloride5-nitro-3-phenyl-indole-2-carboxylic bromide3-(o-chlorophenyl)-5-nitro-indole-2-carboxylic chloride 183*(o-bromopheny1)-5-nitro-indole-Z-carboxylic chloride3-(o-fluorophenyl)-5-nitro-indole-2-carboxylic chloride 3-(p-chlorophenyl )-5 -nitro-in dole-Z-carboxylic chloride3-(m-chlorophenyl)-S-nitro-indole-2-carboxylic chloride EXAMPLE 14 Amixture of 27.5 g. of 5-nitro-3-phenyl-indole2- carboxylic acid and 1 15g. of thionyl chloride is heated under reflux for 30 min. The excess ofthionyl chloride is removed under reduced pressure and the residue isdissolved in 400 ml. of anhydrous tetrahydrofuran. Gaseous ammonia isintroduced into the solution under ice-cooling. The precipitate iscollected by filtration, washed with water and then ethanol, and driedto give 14.5 g. of 5-nitro-3-phenyl-indole-2-carboxamide, m.p. 299 302C.The tetrahydrofuran layer is concentrated to dryness under reducedpressure and the residue is washed with water, ethanol and ethersuccessively, and dried to give an additional 12.1 g. of S-nitro-3-pheny1-indo1e-2-carboxamide, m.p. 295.5 297C. Recrystallization frommethanol affords the analytical sample, m.p. 302C.

Anal. Cald. for C 1-l O N C, 64.05; H, 3.94; N,

14.94%. Found: C, 64.13; H, 3.89; N, 14.15%.

EXAMPLE 15 A mixture of 168.0 g. of 5-nitro-3-phenyl-indole 2-carboxylic acid and 710 g. of thionyl chloride is heated under refluxfor 1.5 hours. The excess thionyl chloride is removed under reducedpressure and the residue is suspended in 2 l of dry toluene. Gaseousammonia is introduced into the suspension for 2 hours. The precipitateis collected by filtration, washed with water and ether, and dried togive 160.4 g. of 5-nitro-3-phenyl-indole-2-carboxamide.

The following compounds are similarly prepared:

6 (or 4)-nitro-3-phenyl-indole-2-carboxamide7-nitro-3-phenyl-indole-2-carboxamide3-(o#chlorophenyl)-5-nitro-indole-2-carboxamide3-(o-bromophenyl)-5-nitro-indole-2-carboxarnide3-(o-fluorophenyl)'5-nitro-indole-2-carboxamide3-(p-chlorophenyl)-5-nitro-indole-2-carboxamide3-(m-chlorophenyl)-5-nitro-indole-2-carboxamide EXAMPLE 16 A mixture of13.5 g. of 5-nitro-3-phenyl-indole-2- carboxamide and 59 g. ofphosphorous oxychloride is heated under reflux for 30 min. The reactionmixture is poured over crushed ice with stirring. The precipitate iscollected by filtration, washed with water and dried to give 11 g. of5-nitro-3-phenyl-indole-2-carb0nitrile, m.p. 261C. Recrystallizationfrom methanol gives pale yellow needles, m.p. 263 264C.

Analysis Calculated for C15H9O2N3: C, 68.44; H,

3.45; N, 15.94%. Found: C, 68.61; H, 3.07; N, 16.19%.

The following compounds are similarly prepared: 6 (or4)-nitro-3-phenyl-indole-2-carbonitrile7-nitro-3-phenyl-indole-2-carbonitrile3-(o-chlorophenyl)-5-nitro-indole-2-carbonitrile3-(o-bromophenyl)-5-nitr0-indole-2-carbonitrile 3-(o-fluorophenyl)--nitro-indole-2-carbonitrile3-(p-chlorophenyl)-5-nitro-indole-2-carbonitrile3-(m-chlorophenyl)-5-nitro-indole-2-carbonitrile EXAMPLE 17 To asolution of 20 g. of 5-nitro-3-phenyl-indole-2- carbonitrile in 800 ml.of dry tetrahydrofuran is added 5.8 g. of powdered sodium borohydrideand the mixture is stirred at room temperature for 30 min.. To themixture is added dropwise a solution of 30 g. of boron trifluorideetherate in 400 ml. of dry tetrahydrofuran with stirring. The resultantmixture is stirred at room temperature and then heated under reflux for2 hours. The reaction mixture is cooled, acidified with 400 ml. ofpercent hydrochloric acid to decompose the excess hydride, and then themixture is neutralized with 200 ml. of ammonium hydroxide. The organiclayer is separated and the aqueous phase is extracted with ether. Theextracts are combined with the organic layer, washed with saline water,dried over sodium sulfate and evaporated to give 47 g. of crude 2-aminomethyl-Sdnitro-3-phenyl-indole.

The crude product (20.1 g.) is dissolved in acetic acid ml.) and etheris added to the solution. The precipitate is collected by filtration togive 2- aminomethyl-5-nitro-3-phenyl-indole acetate, (6.2 g.), m.p. 174175C. Recrystallization from ethanol gives an analytical sample, m.p.l82- 184C.

Analysis Calculated for C -,H O 'N 'C- ,H O C, 62.37; H, 5.24; N,12.84%. Found: C, 62.61; H, 5.13;N,l2.78%.

The following compounds are similarly prepared:

2-aminomethyl-6 (or 4)-nitro-3-phenyl-indole2-aminomethyl-7-nitro-3-phenyl-indole2-aminomethyl-3-(o-chlorophenyl)-5-nitro-indole2-aminomethyl-3-(o-bromophenyl)-5-nitro-indole2-aminomethyl-3-(o-fluorophenyl)-5-nitro-indole2-aminomethyl-3-(m-chlorophenyl)-5-nitro-indole2-aminomethyl-3-(p-chlorophenyl)-5-nitro-indole and thesehydrochlorides, hydrobromides, sulfate, phosphate and acetates.

EXAMPLE 18 A mixture of l g. of 2-aminomethyl-5-nitro-3-phenyl-indoleacetate, 10 ml. of acetic acid and a solution of l g. of chromicanhydride in 1 ml. of water, is stirred at room temperature overnight.To the reaction mixture is added 20 ml. of water and the mixture isneutralized with ammonium hydroxide. The precipitate is separated anddissolved in methylene chloride containing ethanolic hydrogen chloride.The mixture is concentrated and the residue is dissolved in 10 ml. ofpyridine, and heated under reflux for 20 min. The solvent is removedunder reduced pressure to the residue, which is taken up water,collected by filtration and washed with ethanol to give7-nitro-5-phenyl-l,3- dihydro-ZH-l,4-benzodiazepin-2-one, m.p. 220 222C.Recrystallization raised the m.p. to 224 225C.

The following compounds are similarly prepared: 8-nitro-5-phenyll,3-dihydro-2H- 1 ,4-benzodiazepin- 2-one9-nitro-5-phenyl-l,3-dihydro-2H-1,4-benzodiazepin- 2-one5-(o-chlorophenyl)-7-nitrol ,3-dihydro-2H- l ,4-

benzodiazepin-Z-one S-(o-bromophenyl)-7-nitro-1,3-dihydro-2H-l ,4-

benzodiazepin-2-one 5-(o-fluorophenyl)-7-nitro-1,3-dihydro-2H-l ,4-

benzodiazepin-Z-one 5-(m-chlorophenyl)-7-nitro-1,3-dihydro-2H-l,4-

benzodiazepin-Z-one S-(p-chlorophenyl )-7-nitro-l ,3-dihydro-2l-ll ,4-

benzodiazepin-Z-one. We claim: 1. A 2-aminomethylindole derivativerepresented by the formula,

N NO: I

